CommentaryCan Tissue-Based Immune Markers be Used for Studying the Natural History of Cancer?
Section snippets
Introduction: Immunity and Cancer
Since the introduction of Burnet and Thomas’ cancer immunosurveillance hypothesis (1), the concept that the immune system plays a protective role in tumor development has been vigorously debated. The central principle of the hypothesis that the immune system can indeed prevent tumor formation was supported by clinical observations of higher incidences of cancer in immunodepressed individuals (2). Conversely, accumulated evidence showed that infectious and noninfectious causes of local chronic
Important Research Questions in Tumor Immunoepidemiology
Many epidemiologic studies only collect tissue specimens at a single time point, typically the time of diagnosis or selection into the study, which potentially limits the research questions that can be addressed. One of the most explored research questions in individuals with disease has been this: What is the association between the presence of certain immune infiltrates and clinical outcomes such as prognosis and survival? Such analyses have been reported in several solid cancers, including
Why Tissue-Based Markers?
Broadly defined, tissue-based immune markers may refer to markers of specific immune cell populations, the expression of specific cytokines in tissues by immune cells that play a role in immune function or signaling, cytokine receptors, or immune presentation molecules (human leukocyte antigen). Tissue-based markers are likely to become more and more available given the increasing use of biomarkers in clinical care and advances in biomarker discovery and technological innovation (14).
Examples of Tissue-Based Immune Markers
Immune cells and the cellular factors produced from them, both immunosuppressive and inflammatory cytokines, play dual roles in promoting or discouraging cancer development. Their role may be determined by the tumor microenvironment and the events that lead to the initial propagation of carcinogenesis. Of the plethora of cells, cytokines, or other soluble factors involved, tumor-associated macrophages or myeloid-derived suppressive cells and secreted cytokines interleukin (IL)-6, tumor necrosis
Tools for Studying Tissue-Based Immune Markers
Immunity and inflammation at the cancer site can be evaluated using various molecular techniques, depending on the type of tissue that is available and the assessments desired (Table 1 lists some examples described here). The type, density, and location of immune cells can be assessed in fresh and ethanol- or formalin-fixed tumor tissues. Previous studies [e.g., 7, 8, 28, 29, 30, 31, 32, 33] have semiquantitatively evaluated the numbers and proportion of various immune cell subsets, including
Study Populations and Study Design
One of the first considerations of study design is the choice of the most appropriate population for evaluating the question of interest. Importantly, studies in the general population allow for conclusions regarding interventions that may affect public health, such as cancer screening. However, in-depth studies of biological mechanisms might require studies in special populations at high risk for certain outcomes of interest (e.g., referral clinic patients).
Several study designs can be applied
Efficiency for Studying Tissue-Base Immune Markers: Prospective Versus Cross-Sectional Design
Prospective data from cohorts or trials are often preferable because temporality may potentially be evaluated. For tissue-based studies, however, cross-sectional designs in high-risk populations may be more feasible and efficient. A comparison of two National Cancer Institute studies of cervical cancer, the Guanacaste Project and the Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED), provides an excellent example. The Guanacaste Project is a cohort study that began
Sample Size Considerations
Four quantities are needed to calculate sample sizes: (1) the expected difference (e.g., mean difference) or association (e.g., odds ratio), (2) an estimate of the variability in the measurements (e.g., standard deviation, standard error, or 95% confidence interval), (3) the desired statistical power (e.g., 0.8 or 0.9), and (4) the number of comparisons and whether the comparisons are agnostic (i.e., no a priori hypotheses, and typically numerous) or based on biologically plausible, a priori
Potential Confounders
Studies of immune response must also consider potential confounders. For example, age may be associated with both immunity and cancer. In our previous example of immune markers in precursor lesions, precursors typically occur in individuals at a younger age than cancer, and immunity declines with age (63). Thus, age should be accounted for carefully. Immunity also differs for men and women (64), so it is important to consider gender for non–gender-specific cancers. Race/ethnicity has been
Tissue-Based Immune Markers and the Natural History of Cancer
An important goal is to establish how immune response contributes to the development of cancer. Immune markers that are present at the time of cancer diagnosis may reflect the immune function that contributed to the development of cancer or may be the result of the cancer itself. Therefore, disease effects may be best addressed in subjects with precursor conditions. Comparisons of tissue-based immune markers from low-grade precursor conditions to cancer, as well as the range of stages among
An Integrative Approach
Although tissue-based measures are not without limitations, they contribute to our understanding of the role of immune factors in the development of cancer, especially by combining them with other studies of immune markers that have different strengths and limitations. In particular, genetic studies of polymorphisms in immune pathways provide information on the association between inherited differences in immune-related pathways and cancer risk. For example, polymorphisms in the IL1β and the
Conclusions
Tissue-based studies can be used to examine associations between immune markers and cancer outcomes, evaluate and possibly discover new tumor subtypes, and identify clues to the biological mechanisms that contribute to the development of cancer. For each of these approaches, it is important to consider the characteristics of the study population, choose the most suitable study design, use proper techniques to select study participants and their biological samples, employ validated, reliable
References (93)
Cancer: a biological approach
Br Med J
(1957)Cancer and viral infections in immunocompromised individuals
Int J Cancer
(2009)- et al.
Inflammation and cancer: back to Virchow?
Lancet
(2001) - et al.
Cancer immunoediting: from immunosurveillance to tumor escape
Nat Immunol
(2002) - et al.
Immune infiltration in human tumors: a prognostic factor that should not be ignored
Oncogene
(2010) - et al.
Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy
Cancer Discov
(2011) - et al.
Type, density, and location of immune cells within human colorectal tumors predict clinical outcome
Science
(2006) - et al.
Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA-1 as positive prognostic factors
PLoS ONE
(2009) - et al.
Immune cell infiltrates and prognosis in primary carcinoma of the lung
Lung Cancer
(2000) - et al.
Density of DC-LAMP+ dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor
Cancer Immunol Immunother
(2007)
Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium Studies
J Natl Cancer Inst
Lifestyle factors and microsatellite instability in colorectal cancer: the evolving field of molecular pathological epidemiology
J Natl Cancer Inst
Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review
J Pathol
NCCN Task Force report: evaluating the clinical utility of tumor markers in oncology
J Natl Compr Canc Netw
Dual roles of immune cells and their factors in cancer development and progression
Int J Biol Sci
Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm
Nat Immunol
Different tumor microenvironments contain functionally distinct subsets of macrophages derived from ly6c(high) monocytes
Cancer Res
IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses
Nat Immunol
Immunity, inflammation, and cancer
Cell
Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis
Cancer Cell
Myeloid-derived suppressor cells as regulators of the immune system
Nat Rev Immunol
Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function
Trends Immunol
Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3
J Exp Med
Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival
Nat Med
Th17 and regulatory T cells in mediating and restraining inflammation
Cell
Prognostic significance of activated CD8+ T cell infiltrations within esophageal carcinomas
Cancer Res
Stromal regulatory T-cells are associated with a favourable prognosis in gastric cancer of the cardia
BMC Gastroenterol
Functional attributes of mucosal immunity in cervical intraepithelial neoplasia and effects of HIV infection
Cancer Res
Epidemiologic analysis of histologic cervical inflammation: relationship to human papillomavirus infections
Human Pathol
Stereologic estimation of the total numbers, the composition and the anatomic distribution of lymphocytes in cone biopsies from patients with stage I squamous cell carcinoma of the cervix uteri
APMIS
Higher intratumoral infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in resectable gastric cancer
J Cancer Res Clin Oncol
Prognostic ability of a panel of immunohistochemistry markers-retailoring of an ’old solution’
Breast Cancer Res
Prognostic value of myeloperoxidase in patients with chest pain
N Engl J Med
Immunohistochemistry of the inflammatory response in Propionibacterium acnes endophthalmitis
Arch Ophthalmol
Immunohistochemistry and quantitative analysis of protein expression
Arch Pathol Lab Med
Antibody-based proteomics: fast-tracking molecular diagnostics in oncology
Nat Rev Cancer
Antibody validation
Biotechniques
CD68 is not a macrophage-specific antigen
Ann Rheum Dis
A decade of tissue microarrays: progress in the discovery and validation of cancer biomarkers
J Clin Oncol
Evaluation of the prognostic significance of MSMB and CRISP3 in prostate cancer using automated image analysis
Mod Pathol
Quantitative, fluorescence-based in-situ assessment of protein expression
Methods Mol Biol
Indoleamine 2,3-dioxygenase as a modifier of pathogenic inflammation in cancer and other inflammation-associated diseases
Curr Med Chem
The variation of expression of CD4+ CD25+ Foxp3+ regulatory T cells in patients with Helicobacter pylori infection and eradication
Hepatogastroenterology
Elevated expression of Foxp3 in tumor-infiltrating Treg cells suppresses T-cell proliferation and contributes to gastric cancer progression in a COX-2-dependent manner
Clin Immunol
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